CN108164409A - A kind of 2- benzals -1- indones analog and application - Google Patents
A kind of 2- benzals -1- indones analog and application Download PDFInfo
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- CN108164409A CN108164409A CN201810066623.7A CN201810066623A CN108164409A CN 108164409 A CN108164409 A CN 108164409A CN 201810066623 A CN201810066623 A CN 201810066623A CN 108164409 A CN108164409 A CN 108164409A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
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Abstract
The invention discloses a kind of 2 benzal, 1 indone analog and application, the structure such as formula (I) of 2 benzal, the 1 indone analog is shown, in formula (I), R1Independently selected from various alkoxies, hydroxyl, various halogens, trifluoromethyl or nitro.The present invention is for a kind of 2 benzal 1 indone analog technical field of the chalcone as mother nucleus structure to be replaced to carry out lot of experiments, it carries out largely to replace 2 benzal 1 indone analog design, synthesis, Pharmacological Activity Screening of the chalcone as mother nucleus structure, one kind is obtained to replace 2 benzal 1 indone analog of the chalcone as mother nucleus structure, and 2 benzal, the 1 indone analog of the present invention has efficient, wide spectrum antiphlogistic use.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of 2- benzals -1- indone analogs and preparation method thereof
And application.
Background technology
Inflammation is very common in human body as a kind of important pathologic process, and itself is for external as body
Or a kind of autoimmune response of the stimulation of allosome.And when this response imbalance or excessively response lead to damaging certainly for body
When, just evolve into inflammation.So most of disease is all along with the mediation of inflammation and generation, and the mediation of inflammation and generation
Again so that disease aggravates the damage of body, such as acute lung injury, rheumatic arthritis, diabetic complications, cancer, artery
Atherosis, inflammatory bowel disease etc..During these, proinflammatory factor such as TNF-α, IL-6, IL-1 β etc. play important work
With.Medicine in currently available technology for inflammation is more, a large amount of drug improved technology also occurs, wherein for looking into
The invention and research of your keto analog become the important research field of those skilled in the art.
Xanthohumol (XN) is a kind of chalcone derivative mainly separated from hops, it contains brewing and medicine
Common bitter substance.XN shows extensive bioactivity, including anticancer, anti-oxidant and diabetes prevention and treatment.
In addition, it was reported that the NF- κ B in the RAW264.7 macrophages that XN is stimulated by lowering lipopolysaccharides (LPS) are activated and with another
Outer anti-inflammatory effect.But, the serious problems of XN be its in aqueous solution poor solubility and poor bioavailability (<1%), this
Serious application limitation is produced in pharmaceutical research.1- indones with benzo cyclopentanone skeleton are planted in various edible naturals
The naturally occurring component found in object, and be considered as the useful synthetic molecules of the various carbocyclic rings of synthesis and heterocyclic molecular, it can
It is used to prepare the key intermediate of several drugs and natural products.Studies have shown that the chemical combination with 1- indones part
Object has very strong pharmacological importance, because they have anti-inflammatory, anticancer, anti-oxidant and antibacterial etc., various beneficial biologies are living
Property.
Invention content
The present invention in order to solve the above technical problems, provide a kind of 2- benzals -1- indone analogs and preparation method thereof and
Using the 2- benzal -1- indones analog has efficient, wide spectrum antiphlogistic use.
To reach above-mentioned technical purpose, the technical scheme is that：
A kind of 2- benzals -1- indone analogs, structure is as shown in logical formula (I)：
In formula (I), R1Independently selected from one of various alkoxies, hydroxyl, various halogens, trifluoromethyl or nitro or
Person is multiple (when being multiple, phenyl ring is polysubstituted).
The present inventor, for using replace chalcone as mother nucleus structure 2- benzal -1- indone analog technical fields into
Row lot of experiments is carried out largely to replace 2- benzal -1- indone analog design, conjunction of the chalcone as mother nucleus structure
Into, Pharmacological Activity Screening, the 2- benzal -1- indone analogs that a kind of substitution chalcone is mother nucleus structure, and this hair are obtained
It is bright using replace the 2- benzal -1- indones analog that chalcone is mother nucleus structure have efficiently, the antiphlogistic use of wide spectrum.
In the present invention, the alkoxy " alkoxy " is only made of carbon and hydrogen, oxygen atom, does not contain unsaturation, example
Such as：Methoxyl group, ethyoxyl etc..
In the present invention, " hydroxyl " refers to formula-OH." halogen " is-F ,-Cl ,-Br.
" trifluoromethyl or the nitro " is-CF3、-NO2。
Preferably, the 2- benzal -1- indones analog is any compound in 4a-4t：
The present invention also provides a kind of application of the 2- benzal -1- indone analogs, the 2- benzals -1-
Indone is used to prepare anti-inflammatory drug.
Preferably, the anti-inflammatory drug is for treatment acute lung injury as caused by inflammation or by inflammatory cytokine
Beyond normal amount express and discharge caused by with the relevant disease of inflammation.
As a further preference, it is described to include septicopyemia, rheumatoid arthritis, system with the relevant disease of inflammation
Property lupus erythematosus and related syndromes, osteoarthritis, alimentary canal inflammation, polymyositis, dermatomyositis, vasculitic syndrome,
Urarthritis, neuroinflamation, rheumatic arthritis, chemically pain, inflammatory pain, granuloma, granulomatous angiitis,
Arteritis, scytitis, autoimmune disease, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation
Disease, systemic inflammatory response syndrome, septicemia, infectious shock.
Preferably, the 2- benzal -1- indones analogs are played by inhibiting proinflammatory factor IL-6 and TNF-α
Anti-inflammatory effect.
Preferably, the 2- benzal -1- indones analog is used to inhibit the expression of mRNA in inflammatory cell and send out
Wave anti-inflammatory effect.
The present invention also provides a kind of pharmaceutical preparations, and including active ingredient and pharmaceutic adjuvant, the active ingredient includes
2- benzal -1- indone the analogs.
Preferably, the pharmaceutical preparation for injection, tablet, capsule, aerosol, suppository, film, pill,
Ointment, controlled release agent, sustained release agent or nanometer formulation it is any.
Others embodiment according to the present invention, the present invention relates to a kind of one kind with acute lung injury therapeutic effect
It is described to replace medicine of the chalcone as the 2- benzals -1- indones analog of mother nucleus structure and with inflammation related disease
The cause of disease of disease is caused by inflammation at least partly, and the disease includes but not limited to following disease：Alleviate rheumatoid arthrosis
Inflammation, osteoarthritis, spinal arthropathy, urarthritis, rheumatic arthritis, various chornic arthritis acute attack stage or
The painful swelling of joints symptom of duration；Treat non-arthrosis various soft tissue rheumatic pains, as shoulder pain, tenosynovitis, bursal synovitis,
Injury pain after myalgia and movement；Acute light, moderate pain, e.g., after operation, after wound, strain after, primary dysmenorrhea,
Toothache, headache；Ischemic damage and reperfusion, e.g., cerebral ischemia re-pouring, myocardial ischemia-reperfusion；Atherosclerosis；Hepatitis；Lymph
It is scorching；Pneumonia；Dysentery；Appendicitis.
Compared with the existing technology, 2- benzal -1- indones analog of the invention has better anti-inflammatory activity, especially
There is preferable inhibitory activity to two kinds of inflammatory factors of TNF-α and IL-6.
Description of the drawings
Fig. 1 show one kind of the invention synthesized to replace chalcone similar as the 2- benzal -1- indones of mother nucleus structure
The chemical constitution of object (4a-4t) and the inhibitory activity of embodiment 21.
Fig. 2A show the compounds of this invention 4d and the dose-effect of LPS stimulation RAW 264.7 macrophage release TNF-α is inhibited to close
System.
B show the compounds of this invention 4d and the dose-effect of 264.7 macrophages of the RAW release IL-6 of LPS stimulations is inhibited to close
System.
Fig. 3 A-D show the table for the mRNA that the compounds of this invention 4d inhibits in 264.7 macrophages of RAW of LPS stimulations
It reaches.
Specific embodiment
The specific embodiment of the invention is described in detail below in conjunction with specific attached drawing.It should be noted that in following embodiments
The combination of the technical characteristic or technical characteristic of description is not construed as isolated, they can be combined with each other to reach
To superior technique effect.
A kind of method for preparing above-mentioned 2- benzal -1- indone analogs, includes the following steps：
Compound synthesis general line such as following formula a：
Formula a. is a kind of to replace synthesis general line of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure
Synthesis step (the step a- steps c) of compound (4a-t) in type I：
Step a synthesizes 6-[(tetrahydrochysene-2H- pyrans-2- bases) oxygroup]-2,3- dihydro-1H- 1-Indanones (2)：By 3,4- bis-
Hydrogen -2H- pyrans (2.83g, 33.75mmol) and p-methyl benzenesulfonic acid pyridiniujm (169mg, 0.675mmol) be added to 6- hydroxyls -
In dichloromethane (10ml) solution of 1- indones (1) (1.0g, 6.75mmol), reaction solution is stirred at reflux 4 hours at 40 DEG C.
Vacuum distillation removes solvent after reaction.Residue is dissolved in extraction three in ethyl acetate (30mL) and distilled water (30mL)
Secondary, organic layer is dried with anhydrous magnesium sulfate, and ethyl acetate is removed in vacuum distillation.Residue obtains centre with silica gel column chromatography method
Body 2 (9.96g, yield 92%, colourless liquid).
(Z)-2- benzals-6-[(tetrahydrochysene-2H- pyrans-2- bases) oxygroup]-2,3- dihydros-1H- of step b synthesis substitutions
1-Indanone (3a-b, 3e-t)：Take 6-[(tetrahydrochysene-2H- pyrans-2- bases) oxygroup]-2,3- dihydro-1H- 1-Indanones (2)
(0.05g, 0.22mmol) and various substituted benzaldehydes (0.22mmol) are added in reaction bulb and are dissolved in ethanol solution (10ml),
It is slowly added to 20% sodium hydroxide solution (3.0ml).Reaction bulb is placed in be stirred overnight under room temperature.After reaction, to
Add in ice water in reaction bulb, yellow solid be precipitated, filter, washing, be dried to obtain substituted (Z)-2- benzals-6-[(tetrahydrochysene-
2H- pyrans -2- bases) oxygroup] -2,3- dihydro -1H- 1-Indanones (3a-b, 3e-t) (yield 90-97%, yellow solid).
The general step of step c synthesis final products 4a-4t：By substituted (Z)-2- benzals-6-[(tetrahydrochysene-2H- pyrans-
2- yls) oxygroup] -2,3- dihydro -1H- 1-Indanones (3a-b, 3e-t) are dissolved in methanol/tetrahydrofuran=1：In 1 (5ml) solution,
The hydrochloric acid solution (0.5ml) of 1.0mol/L is slowly added to, is stirred at room temperature, after the completion of thin-layer chromatography monitoring reaction, to reaction bulb
Yellow solid is precipitated in middle addition ice water, filters, and washing, the method for obtaining yellow solid ethyl alcohol recrystallization is further purified can
Obtain the final product 4a-t (gross production rate 40-90%) in type I.
Synthesis (the step d) of compound (4c and 4d) in type I：
The general step of step d synthesis final products 4c and 4d：6- hydroxide radical-1-indenones (1) (3.25g, 21.9mmol) is molten
Solution adds in substituted benzaldehyde (21.9mmol), is then passed through dry hydrogen chloride gas later in ethyl alcohol (50mL).Reaction
Mixture is stirred at room temperature overnight.Ice water is added in into reaction solution after reaction, yellow solid is precipitated, is filtered, washing obtains
The final product 4c and 4d (the gross production rate 40- that can obtain in type I is further purified in method to yellow solid ethyl alcohol recrystallization
90%).(yield 51-53%, yellow solid).
The chemical constitution characterize data of compound 4a synthesized by embodiment 1
Compound (4a):(E) -6- hydroxyls -2- (4- benzylidenes) -2,3- dihydro -1H- 1-Indanones
(E)-6-hydroxy-2-(4-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one
Yellow powder, yield：79.6%, fusing point:226.2-228.3℃.1H NMR(500MHz,DMSO-d6)δ:9.82
(1H, s, Ar-OH), 7.72 (2H, d, J=8.65Hz, ArH2), 7.46 (1H, d, J=8.55Hz, ArH), 7.45 (1H, s, Ar-
), CH=7.12 (1H, d, J=8.13Hz, ArH), 7.06 (1H, s, ArH), 7.05 (2H, d, J=8.84Hz, ArH2),3.93
(2H,s,Ar-CH2-),3.82(3H,s,Ar-OCH3).13C NMR(125MHz,DMSO-d6)δ(ppm):193.18,160.53,
157.10,140.54,138.72,133.58,132.55×2,132.37,127.57,127.31,123.08,114.54×2,
108.11,55.34,31.13.ESI-MS m/z:One kind that 267.28 (M)+are synthesized as shown in Figure 1 for the present invention is looked into replacing
Your ketone is the chemical constitution of the 2- benzal -1- indone analogs of mother nucleus structure.
The chemical constitution characterize data of compound 4b synthesized by embodiment 2
Compound (4b):(E) -6- hydroxyls -2- (4- ethoxybenzylidenes) -2,3- dihydro -1H- 1-Indanones
(E)-2-(4-Ethoxybenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow powder, yield:58.3%, fusing point:220.4-222.6℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
7.71 (2H, d, J=8.50Hz, ArH2), 7.47 (1H, d, J=9.03Hz, ArH), 7.45 (1H, s, Ar-CH=), 7.12
(1H, d, J=8.15Hz, ArH), 7.07 (1H, s, ArH), 7.03 (2H, d, J=8.50Hz, ArH2),4.09(2H,m,Ar-O-
CH2-),3.93(2H,s,Ar-CH2), 1.34 (3H, t, J=6.80Hz, Ar-OCH2-CH3).13C NMR(125MHz,DMSO-
d6)δ(ppm):193.18,159.83,157.10,140.53,138.73,133.49,132.57×2,132.40,127.42,
127.31,123.06,114.94×2,108.11,63.31,31.14,14.50.ESI-MS m/z:281.18(M)+Such as Fig. 1
One kind of the invention synthesized is shown so that chemistry of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure to be replaced to tie
Structure.
The chemical constitution characterize data of compound 4e synthesized by embodiment 3
Compound (4e):(E) -2- (2,3- dimethoxybenzylidenegroup groups) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(2,3-dimethoxybenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow powder, yield:68.3%, fusing point:161.2-163.6℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.85 (1H, s, Ar-OH), 7.77 (1H, s, Ar-CH=), 7.46 (1H, d, J=8.05Hz, ArH), 7.38 (1H, d, J=
7.11Hz,ArH),7.20-7.13(3H,m,ArH),7.07(1H,s,ArH),3.93(2H,s,Ar-CH2-),3.84(3H,s,
Ar-OCH3),3.78(3H,s,Ar-OCH3).13C NMR(125MHz,DMSO-d6)δ(ppm):193.28,157.13,152.66,
148.73,140.85,138.46,136.77,128.66,127.41,126.31,124.27,123.45,120.99,114.52,
108.14,60.95,55.80,30.94.ESI-MS m/z:297.17 (M)+as shown in Figure 1 for the present invention synthesize it is a kind of with
Replace chemical constitution of the chalcone for the 2- benzal -1- indone analogs of mother nucleus structure.
The chemical constitution characterize data of compound 4f synthesized by embodiment 4
Compound (4f)：(E) -2- (2,4- dimethoxybenzylidenegroup groups) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(2,4-Dimethoxybenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow powder, yield：60.9%, fusing point:164.3-166.6℃.1H NMR(500MHz,DMSO-d6)δ:7.82
(1H, s, Ar-CH=), 7.71 (1H, d, J=9.34Hz, ArH), 7.45 (1H, d, J=8.21Hz, ArH), 7.11 (1H, d, J
=8.16Hz, ArH), 7.06 (1H, s, ArH), 6.66 (1H, s, ArH), 6.66 (1H, d, J=7.00Hz, ArH), 3.89 (2H,
s,Ar-CH2-),3.89(3H,s,Ar-OCH3),3.84(3H,s,Ar-OCH3).13C NMR(125MHz,DMSO-d6)δ(ppm):
193.18,162.35,160.26,157.04,140.52,138.86,132.99,130.74,127.25,126.36,122.90,
116.28,108.10,106.13,98.38,55.84,55.47,31.15.ESI-MSm/z:297.17 (M)+are as shown in Figure 1
One kind that the present invention synthesizes is to replace chemical constitution of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure.
The chemical constitution characterize data of compound 4g synthesized by embodiment 5
Compound (4g):(E) -6- hydroxyls -2- (3,4,5- trimethoxies benzal) -2,3- dihydro -1H- 1-Indanones
(E)-6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-2,3-dihydro-1H-inden-1-
one
Yellow powder, yield：82.3%, fusing point：184.3-186.5℃.1H NMR(500MHz,DMSO-d6)δ:9.85
(1H, s, Ar-OH), 7.49 (1H, d, J=8.22Hz, ArH), 7.46 (1H, s, Ar-CH=), 7.14 (1H, d, J=8.17Hz,
ArH),7.08(3H,s,ArH),4.03(2H,s,Ar-CH2-),3.87(6H,s,Ar-OCH3),3.73(3H,s,Ar-OCH3)
.13C NMR(125MHz,DMSO-d6)δ(ppm):193.22,157.13,153.01×2,140.73,139.16,138.54,
135.09,132.81,130.43,127.35,123.32,108.36×2,108.15,60.12,56.02×2,30.82.ESI-
MS m/z:327.25 (M)+are one kind of the invention synthesized as shown in Figure 1 to replace 2- benzal of the chalcone as mother nucleus structure
The chemical constitution of base -1- indone analogs.
The chemical constitution characterize data of compound 4h synthesized by embodiment 6
Compound (4h):(E) -6- hydroxyls -2- (2,3,4- trimethoxies benzal) -2,3- dihydro -1H- 1-Indanones
(E)-6-Hydroxy-2-(2,3,4-trimethoxybenzylidene)-2,3-dihydro-1H-inden-1-
one
Yellow solid, yield：67.2%, fusing point：165.8-166.6℃.1H NMR(500MHz,DMSO-d6)δ:9.81
(1H, s, Ar-OH), 7.71 (1H, s, Ar-CH=), 7.53 (1H, d, J=8.93Hz, ArH), 7.46 (1H, d, J=8.22Hz,
), ArH 7.12 (1H, d, J=8.17Hz, ArH), 7.06 (1H, s, ArH), 6.94 (1H, d, J=8.92Hz, ArH), 3.90
(2H,s,Ar-CH2-),3.87(3H,s,Ar-OCH3),3.85(3H,s,Ar-OCH3),3.77(3H,s,Ar-OCH3).13C NMR
(125MHz,DMSO-d6)δ(ppm):193.17,157.10,155.14,153.56,141.89,140.60,138.69,
134.51,127.31,126.28,124.77,123.12,121.42,108.34,108.12,61.61,60.44,56.01,
31.08.ESI-MS m/z:327.19 (M)+are one kind of the invention synthesized as shown in Figure 1 to replace chalcone as mother nucleus structure
2- benzal -1- indone analogs chemical constitution.
The chemical constitution characterize data of compound 4i synthesized by embodiment 7
Compound (4i):(E) -6- hydroxyls -2- (2,4,6- trimethoxies benzal) -2,3- dihydro -1H- 1-Indanones
(E)-6-Hydroxy-2-(2,4,6-trimethoxybenzylidene)-2,3-dihydro-1H-inden-1-
one
Yellow solid, yield：68.7%, fusing point：165.3-167.2℃.1H NMR(500MHz,DMSO-d6)δ:9.74
(1H, s, Ar-OH), 7.53 (1H, s, Ar-CH=), 7.38 (1H, d, J=7.50Hz, ArH), 7.08 (1H, d, J=7.50Hz,
ArH),7.03(1H,s,ArH),6.31(2H,s,ArH2),3.84(9H,s,Ar-OCH3),3.54(2H,s,Ar-CH2-).13C
NMR(125MHz,DMSO-d6)δ(ppm):193.12,162.67,159.32×2,156.83,140.46,138.98,
136.45,127.14,126.08,122.94,107.97,105.21,90.87×2,55.69×2,55.44,31.61.ESI-
MS m/z:326.93 (M)+are one kind of the invention synthesized as shown in Figure 1 to replace 2- benzal of the chalcone as mother nucleus structure
The chemical constitution of base -1- indones.
The chemical constitution characterize data of compound 4j synthesized by embodiment 8
Compound (4j):(E) -6- hydroxyls -2- (2,4,5- trimethoxies benzal) -2,3- dihydro -1H- 1-Indanones
(E)-6-Hydroxy-2-(2,4,5-trimethoxybenzylidene)-2,3-dihydro-1H-inden-1-
one
Yellow solid, yield：59.4%, fusing point：161.2-163.5℃.1H NMR(500MHz,DMSO-d6)δ:9.79
(1H, s, Ar-OH), 7.84 (1H, s, Ar-CH=), 7.47 (1H, d, J=8.01Hz, ArH), 7.28 (1H, s, ArH), 7.11
(1H, d, J=7.50Hz, ArH), 7.06 (1H, s, ArH), 6.77 (1H, s, ArH), 3.97 (2H, s, Ar-CH2-),3.90
(3H,s,Ar-OCH3),3.88(3H,s,Ar-OCH3),3.82(3H,s,Ar-OCH3).13C NMR(125MHz,DMSO-d6)δ
(ppm):193.18,157.02,154.72,152.09,142.79,140.52,138.89,132.70,127.24,126.54,
122.87,114.71,112.88,108.06,97.74,56.45,56.28,55.82,30.90.ESI-MS m/z:327.25
(M)+is one kind of the invention synthesized as shown in Figure 1 to replace 2- benzal -1- indone analog of the chalcone as mother nucleus structure
Chemical constitution.
The chemical constitution characterize data of compound 4k synthesized by embodiment 9
Compound (4k):(E) -2- (2- fluorine benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanone (E) -2- (2-
Fluorobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：43.9%, fusing point：196.4-198.9℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.88 (1H, s, Ar-OH), 7.89 (1H, t, J=7.71Hz, ArH), 7.62 (1H, s, Ar-CH=), 7.54-7.46 (2H, m,
ArH2),7.37-7.32(2H,m,ArH2), 7.17 (1H, d, J=8.20Hz, ArH), 7.10 (1H, s, ArH), 3.99 (2H, s,
Ar-CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):192.93,157.21,140.87,138.22,138.05,
131.83,131.76,130.10,127.43,124.91,123.73,122.87,115.95,115.78,108.25,
30.84.ESI-MS m/z:255.14 (M)+are one kind of the invention synthesized as shown in Figure 1 to replace chalcone as mother nucleus structure
2- benzal -1- indone analogs chemical constitution.
The chemical constitution characterize data of compound 4l synthesized by embodiment 10
Compound (4l):(E) -2- (2- chlorine benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E) -2- (2-Chlorobenzylidene) -6-hydroxy-2,3-dihydro-1H-inden-1-one yellow
Solid, yield：48.6%, fusing point:232.1-234.3℃.1H NMR(500MHz,DMSO-d6)δ(ppm):9.89(1H,s,Ar-
), OH 7.92 (1H, d, J=6.45Hz, ArH), 7.77 (1H, s, Ar-CH=), 7.60 (1H, d, J=7.23Hz, ArH),
7.50-7.44(3H,m,ArH3), 7.17 (1H, d, J=7.92Hz, ArH), 7.10 (1H, s, ArH), 3.97 (2H, s, Ar-
CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):192.97,157.22,141.02,138.55,138.21,134.79,
132.58,131.00,130.37,129.98,127.60,127.45,127.36,123.79,108.25,30.55.ESI-MS
m/z:271.06(M)+.
It is a kind of to replace 2- benzal -1- indone class of the chalcone as mother nucleus structure be as shown in Figure 1 that the present invention synthesizes
Like the chemical constitution of object.
The chemical constitution characterize data of compound 4m synthesized by embodiment 11
Compound (4m):(E) -2- (2- bromines benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(2-Bromobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：45.7%, fusing point:226.4-228.1℃.1H NMR(500MHz,DMSO-d6)δ:9.89
(1H, s, Ar-OH), 7.90 (1H, d, J=7.70Hz, ArH), 7.77 (1H, d, J=8.03Hz, ArH), 7.71 (1H, s, Ar-
), CH=7.52 (1H, t, J=7.50Hz, ArH), 7.47 (1H, d, J=8.23Hz, ArH), 7.37 (1H, t, J=7.90Hz,
ArH).13C NMR(125MHz,DMSO-d6)δ(ppm):192.95,157.22,141.05,138.51,138.23,134.25,
133.24,131.15,130.49,130.17,128.13,127.46,125.72,123.79,108.24,30.40.ESI-MS
m/z:315.05 (M)+are one kind of the invention synthesized as shown in Figure 1 to replace 2- benzal -1- of the chalcone as mother nucleus structure
The chemical constitution of indone analog.
The chemical constitution characterize data of compound 4n synthesized by embodiment 12
Compound (4n):(E) -2- (3- bromines benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(3-Bromobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：55.2%, fusing point:184.2-186.7℃.1H NMR(500MHz,DMSO-d6)δ:7.95
(1H, s, Ar-CH=), 7.78 (1H, d, J=7.70Hz, ArH), 7.64 (1H, d, J=7.89Hz, ArH), 7.50 (1H, d, J
=8.22Hz, ArH), 7.47 (1H, d, J=7.32Hz, ArH), 7.45 (1H, t, J=8.25Hz, ArH), 7.16 (1H, d, J=
8.15Hz,ArH),7.09(1H,s,ArH),4.00(2H,s,Ar-CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):
193.12,157.20,140.87,138.24,137.56,137.41,132.79,132.18,130.95,130.65,129.40,
127.48,123.67,122.23,108.18,30.93.ESI-MS m/z:316.94 (M)+are as shown in Figure 1 present invention synthesis
One kind to replace chemical constitution of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure.
The chemical constitution characterize data of compound 4o synthesized by embodiment 13
Compound (4o):(E) -2- (4- bromines benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(4-Bromobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：44.6%, fusing point：243.6-245.4℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.86 (1H, s, Ar-OH), 7.71 (2H, d, J=8.75Hz, ArH2), 7.70 (2H, d, J=8.68Hz, ArH2),7.48(1H,
S, Ar-CH=), 7.46 (1H, d, J=5.03Hz, ArH), 7.15 (1H, d, J=8.20Hz, ArH), 7.07 (1H, s, ArH),
3.96(2H,s,Ar-CH2-).13CNMR(125MHz,DMSO-d6)δ(ppm):193.14,157.20,140.72,138.35,
136.88,134.19,132.45×2,131.90×2,131.03,127.39,123.58,123.12,108.20,
31.04.ESI-MS m/z:315.05 (M)+are one kind of the invention synthesized as shown in Figure 1 to replace chalcone as mother nucleus structure
2- benzal -1- indone analogs chemical constitution.
The chemical constitution characterize data of compound 4p synthesized by embodiment 14
Compound (4p):(E) -2- (4- fluorine benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(4-Fluorobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：41.8%, fusing point:220.9-222.9℃1H NMR(500MHz,DMSO-d6)δ(ppm):
9.84(1H,s,Ar-OH),7.83(2H,s,ArH2), 7.49 (1H, s, Ar-CH=), 7.47 (1H, d, J=9.17Hz, ArH),
7.35-7.26(2H,m,ArH2), 7.14 (1H, d, J=5.30Hz, ArH), 7.08 (1H, s, ArH), 3.97 (2H, s, Ar-
CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):193.19,157.17,140.74,138.42,135.77,132.97,
132.91,131.61,131.58,131.18,127.37,123.44,116.06,115.89,108.19,30.96.ESI-MS
m/z:255.07(M)+It is a kind of to replace 2- benzal -1- of the chalcone as mother nucleus structure be as shown in Figure 1 that the present invention synthesizes
The chemical constitution of indone analog.
The chemical constitution characterize data of compound 4q synthesized by embodiment 15
Compound (4q):(E) -2- (3,4- difluoros benzylidene) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(3,4-Difluorobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：48.4%, fusing point:221.4-223.6℃.1H NMR(500MHz,DMSO-d6)δ:9.84
(1H, s, Ar-OH), 7.85 (1H, t, J=9.68Hz, ArH), 7.64 (1H, s, ArH), 7.57-7.52 (1H, m, ArH), 7.48
(1H, d, J=9.16Hz, ArH), 7.47 (1H, s, Ar-CH=), 7.16 (1H, d, J=8.08Hz, ArH), 7.08 (1H, s,
ArH),3.99(2H,s,Ar-CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):193.09,157.20,140.82,
138.22,137.07,130.13,128.00,127.97,127.40,123.64,119.14,119.00,118.09,117.95,
108.20,30.76.ESI-MS m/z:273.09 (M)+be as shown in Figure 1 the present invention synthesize it is a kind of using replace chalcone as
The chemical constitution of the 2- benzal -1- indone analogs of mother nucleus structure.
The chemical constitution characterize data of compound 4r synthesized by embodiment 16
Compound (4r):(E) -2- (3,4- dichloros benzylidene) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(3,4-Dichlorobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：54.3%, fusing point:220.1-222.3℃.1H NMR(500MHz,DMSO-d6)δ:8.01
(1H, s, Ar-CH=), 7.78-7.72 (2H, m, ArH2), 7.49 (1H, d, J=8.00Hz, ArH), 7.46 (1H, s, ArH),
7.16 (1H, d, J=7.20Hz, ArH), 7.08 (1H, s, ArH), 4.00 (2H, s, Ar-CH2-).13C NMR(125MHz,
DMSO-d6)δ(ppm):193.03,157.22,140.81,138.17,138.06,135.74,132.04,132.00,
131.69,130.97,130.30,129.66,127.45,123.75,108.20,30.84.ESI-MS m/z:305.07(M)+.
It is a kind of to replace change of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure be as shown in Figure 1 that the present invention synthesizes
Learn structure.
The chemical constitution characterize data of compound 4s synthesized by embodiment 17
Compound (4s):(E) -6- hydroxyls -2- [4- (trifluoromethyl) benzal] -2,3- dihydro -1H- 1-Indanones
(E)-6-Hydroxy-2-[4-(trifluoromethyl)benzylidene]-2,3-dihydro-1H-
inden-1-one
Yellow solid, yield：48.9%, fusing point:210.8-212.3℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.89 (1H, s, Ar-OH), 7.96 (2H, d, J=8.04Hz, ArH), 7.92 (2H, d, J=8.11Hz, ArH), 7.54 (1H, s,
), Ar-CH=7.48 (2H, d, J=8.22Hz, ArH), 7.16 (1H, d, J=8.16Hz, ArH), 7.09 (1H, s, ArH),
4.02(2H,s,Ar-CH2-).13CNMR(125MHz,DMSO-d6)δ(ppm):193.11,157.25,140.88,138.95,
138.60,138.18,131.06×2,130.44×2,127.44,125.63,125.60,123.80,108.24,
31.00.ESI-MS m/z:305.13(M)+.
It is a kind of to replace 2- benzal -1- indone class of the chalcone as mother nucleus structure be as shown in Figure 1 that the present invention synthesizes
Like the chemical constitution of object.
The chemical constitution characterize data of compound 4t synthesized by embodiment 18
Compound (4t):(E) -2- (the chloro- 3- nitrobenzals of 4-) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(4-chloro-3-nitrobenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-
one
Yellow solid, yield：51.4%, fusing point:241.3-242.9℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.88 (1H, s, Ar-OH), 8.39 (1H, s, ArH), 8.05 (1H, s, ArH), 7.86 (1H, s, Ar-CH=), 7.51 (2H, s,
ArH),7.15(1H,s,ArH),7.06(1H,s,ArH),4.01(2H,s,Ar-CH2-).13C NMR(125MHz,DMSO-d6)δ
(ppm):192.94,157.28,148.07,140.82,139.12,138.07,135.52,134.97,131.97,128.79,
127.44,126.53,125.23,123.93,108.263,30.75.ESI-MS m/z:316.03(M)+.
It is a kind of to replace 2- benzal -1- indone class of the chalcone as mother nucleus structure be as shown in Figure 1 that the present invention synthesizes
Like the chemical constitution of object.
The chemical constitution characterize data of compound 4c synthesized by embodiment 19
Compound (4c):(E) -2- (3,4- dihydroxy benzal) -6- hydroxyl -2,3- dihydro -1H- 1-Indanones
(E)-2-(3,4-dihydroxybenzylidene)-6-hydroxy-2,3-dihydro-1H-inden-1-one
Yellow solid, yield：51.2%, fusing point:230.2-232.6℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.81 (1H, s, Ar-OH), 9.66 (1H, s, Ar-OH), 9.27 (1H, s, Ar-OH), 7.47 (1H, d, J=8.18Hz, ArH),
7.35 (1H, s, Ar-CH=), 7.21 (1H, s, ArH), 7.12 (2H, t, J=8.69Hz, ArH2),7.07(1H,s,ArH),
6.86 (1H, d, J=8.18Hz, ArH), 3.90 (2H, s, Ar-CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):
193.13,157.07,147.91,145.57,140.37,138.89,133.33,132.37,127.26,126.48,124.12,
122.87,117.43,116.02,108.07,31.23.ESI-MS m/z:269.11 (M)+are as shown in Figure 1 present invention synthesis
One kind to replace chemical constitution of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure.
The chemical constitution characterize data of compound 4d synthesized by embodiment 20
Compound (4d):(E) -6- hydroxyls -2- (4- hydroxy-3-methoxies benzal) -2,3- dihydro -1H- 1-Indanones
(E)-6-hydroxy-2-(4-hydroxy-3-methoxybenzylidene)-2,3-dihydro-1H-
inden-1-one
Yellow solid, yield：53.4%, fusing point:229.3-232.5℃.1H NMR(500MHz,DMSO-d6)δ(ppm):
9.80 (1H, s, Ar-OH), 9.72 (1H, s, Ar-OH), 7.47 (1H, d, J=8.22Hz, ArH), 7.43 (1H, s, Ar-CH
=), 7.32 (1H, s, ArH), 7.25 (1H, d, J=8.34Hz, ArH), 7.12 (1H, d, J=8.17Hz, ArH), 7.06 (1H,
S, ArH), 6.90 (1H, d, J=8.22Hz, ArH), 3.96 (2H, s, Ar-CH2-),3.86(3H,s,Ar-OCH3).13C NMR
(125MHz,DMSO-d6)δ(ppm):193.16,157.06,148.86,147.79,140.49,138.85,133.28,
132.73,127.27,126.50,124.92,122.93,115.94,114.70,108.08,55.68,31.07.ESI-MS m/
z:283.9(M+1)+It is a kind of to replace 2- benzal -1- of the chalcone as mother nucleus structure be as shown in Figure 1 that the present invention synthesizes
The chemical constitution of indone analog.2- benzals -1- indones the analog of 21 present invention of embodiment stimulates lipopolysaccharides (LPS) huge
The activity of the inhibition of phagocyte release inflammatory factor
The compound stimulation RAW 264.7 macrophage release inflammatory factors that the embodiment of the present invention 1~20 is prepared
(TNF-α and IL-6), the method for inhibition test the external preliminary anti-inflammatory activity of compound, and specific method is as follows：1.2×106
A 264.7 macrophages of RAW are incubated at 37 DEG C with DMEM culture solutions, culture solution are updated after 24 hours, and add in tested compounds
(final concentration of 10 μM) pre-process 2 hours, then are continued with 22 hours with the LPS of 0.5 μ g/mL, collect culture solution ELISA method
Detect TNF-α and IL-6 contents；Collect cell detection total protein concentration, ELISA results with corresponding total protein concentration be divided by compared with
Standard, with the TNF-α of LPS control groups and the calibration of IL-6 contents for 100；Each compound retest 3 times calculate average value and mistake
Difference.It is compareed during test with positive drug xanthohumol.The inhibitory activity that compound discharges TNF-α and IL-6 as shown in Figure 1,
2- benzals -1- indones analog of the invention stimulates 264.7 macrophages of RAW to lipopolysaccharides (LPS) as can be seen from this figure
The inhibitory activity of IL-6 and TNF-α is discharged, inhibitory activity computational methods are as follows：[1- (A sample-A blank)/(A controls-A is empty
In vain)] * 100%, wherein, the expression of A samples adds untested compound and the data of LPS, and A controls represent to add in the number of independent LPS
According to the expression of A blank is not added with untested compound and the data of LPS.
The embodiment of the present invention 1~20 prepare to replace chalcone similar as the 2- benzal -1- indones of mother nucleus structure
Object majority of compounds is respectively provided with the inhibitory activity preferably discharged to IL-6, has preferable inhibit for the release of TNF-a
Effect is 4d.
The 4d that 22 embodiment 20 of embodiment is prepared inhibits LPS 264.7 macrophages of stimulation RAW release IL-6 and TNF-α
Dose-effect relationship
Further test the 4d that embodiment 20 prepares inhibit LPS 264.7 macrophages of stimulation RAW release TNF-α and
The dose-effect relationship of IL-6, method：With embodiment 21.Experimental data is shown in Fig. 2.In Fig. 2, ordinate is opposite burst size, opposite to release
High-volume computational methods are as follows：[(A sample-A blank)/(A control-A blank)] * 100%, wherein, the expression of A samples adds to be measured
The data of compound and LPS, A controls represent the data of the independent LPS of addition, and the expression of A blank is not added with untested compound and the number of LPS
According to.
Compound 4d is respectively provided with preferable dose-effect relationship to the inhibitory activity of TNF-α and IL-6.It is as shown in Figure 2 the present invention
Compound 4d inhibits the dose-effect relationship of LPS 264.7 macrophages of stimulation RAW release IL-6 and TNF-α.
The 4d that 23 embodiment 20 of embodiment is prepared inhibits the expression of the mRNA in the macrophage of LPS stimulations
In order to determine whether the reduction of the macrophage of LPS inductions is related with Transcription inhibition, passes through real-time quantitative PCR (RT-
QPCR) method measures the mRNA of TNF-α, IL-6, IL-1 β and Intercellular Adhesion Molecule 1 (ICAM-1).With LPS (1.0mg/
ML) processing macrophage 6 hours, with compound 4d processing or the expression without compound before processing inflammation gene expression.As a result it summarizes
In figures 3 a-d, their TNF-α, IL-6 are clearly illustrated, IL-1 β and ICAM-1 are lowered.Compound 4d can be lowered effectively
TNF-α, IL-6, the expression of IL-1 β and ICAM-1 have statistical significance.These data provide 2- benzal -1- indone classes
Like the anti-inflammatory effect of object 4d and the evidence of influence mRNA level in-site.
Embodiment 24
It is a kind of containing one kind to replace pharmaceutical composition of the chalcone as the 2- benzal -1- indone analogs of mother nucleus structure
Object, the pharmaceutical composition include active ingredient and pharmaceutic adjuvant, and the active ingredient is one kind to replace chalcone as parent nucleus knot
Several or several compositions in the 2- benzals -1- indones analog and its officinal salt of structure, it is described a kind of to replace chalcone
2- benzal -1- indones analog for mother nucleus structure has general formula：
Wherein：In type I, R1Independently selected from various alkoxies, hydroxyl, various halogens, trifluoromethyl or nitro.
It is characterized in that, any compound in following 4a-t：
The pharmaceutical composition of the present invention can be used in combination with the anti-inflammatory drug listed, the prevention inflammation disease being prepared
The composition of sick class drug, the anti-inflammatory drug listed include various Steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drug；Medicine
Acceptable salt is some such salt on, they keep the ideal bioactivity of parent compound, and are not given to not
Desired toxicological action, the example of such salt includes the salt formed with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid
Deng；The salt formed with organic acid, such as acetic acid, oxalic acid, tartaric acid, maleic acid, citric acid, ascorbic acid；And by element the moon
The salt that ion is formed, such as chlorine, bromine and iodine；
Pharmaceutic adjuvant in pharmaceutical composition of the present invention refers to the pharmaceutical carrier of pharmaceutical field routine, including but not limited to any
By Food and Drug Administration be approved as being acceptable for the adjuvant of people or domestic animal, carrier, excipient, glidant, sweetener,
It is diluent, preservative, dyestuff/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic
Agent, solvent or emulsifier.
The preparation of the present invention includes those and is suitable for oral, rectum, part, oral cavity, sublingual, parenteral (for example, subcutaneous, flesh
It is meat, intravenous) and percutaneous dosing preparation, although in any given case, optimum route will depend on being controlled
The property and seriousness of the illness for the treatment of and the property depending on used particular active compounds.
By the above embodiment of the present invention it is found that present invention offer is a kind of to have one kind to replace chalcone as mother nucleus structure
2- benzals -1- indones analog and purposes carry out many experiments for 2- benzal -1- indone analogs technical field and grind
Study carefully, carry out a large amount of a kind of 2- benzal -1- indone analog design, synthesis, pharmacology of the chalcone as mother nucleus structure to be replaced to live
Property screening, obtain the present invention it is a kind of have it is a kind of to replace 2- benzal -1- indone analog of the chalcone as mother nucleus structure, and
And the present invention have it is a kind of to replace 2- benzals -1- indones analog that chalcone is mother nucleus structure with efficient, wide spectrum
Antiphlogistic use.The present invention also provides it is a kind of containing one kind to replace 2- benzal -1- indone class of the chalcone as mother nucleus structure
Like the pharmaceutical composition of object, which has efficient, wide spectrum antiphlogistic use.
Above-mentioned detailed description is illustrating for the possible embodiments invented, which is not to limit this hair
Bright the scope of the claims, all equivalence enforcements or change without departing from the present invention should all be contained in the scope of the claims of the present invention.
In addition, those skilled in the art can also the claims in the present invention scope of disclosure and spirit in do other forms and
Various modifications, addition and replacement in details.Certainly, these spirit is done according to the present invention various modifications, addition and replacements
Deng variation, should all include within scope of the present invention.
Claims (10)
1. a kind of 2- benzals -1- indone analogs, which is characterized in that structure such as logical formula (I)
In formula (I), R1One or more in alkoxy, hydroxyl, halogen, trifluoromethyl or nitro.
2. 2- benzals -1- indone analogs according to claim 1, which is characterized in that the R1For C1~C5Alcoxyl
One or more in base, hydroxyl, F, Cl, Br, trifluoromethyl or nitro.
3. 2- benzals -1- indone analogs according to claim 1, which is characterized in that anyization in 4a-4t
Close object：
It is 4. a kind of such as the application of claims 1 to 3 any one of them 2- benzal -1- indone analogs, which is characterized in that institute
2- benzal -1- the indones stated are used to prepare anti-inflammatory drug.
5. the application of 2- benzals -1- indone analogs according to claim 4, which is characterized in that the anti-inflammatory agent
Caused by object is for treating the acute lung injury as caused by inflammation or being exceeded normal amount expression by inflammatory cytokine and discharged
With the relevant disease of inflammation.
6. the application of 2- benzals -1- indone analogs according to claim 5, which is characterized in that described with inflammation phase
The disease of pass includes septicopyemia, rheumatoid arthritis, systemic loupus erythematosus and related syndromes, osteoarthritis, digestion
Road inflammation, polymyositis, dermatomyositis, vasculitic syndrome, urarthritis, neuroinflamation, rheumatic arthritis, change
The property learned pain, inflammatory pain, granuloma, granulomatous angiitis, arteritis, scytitis, autoimmune disease, adipose membrane
Inflammation, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatory response syndrome, septicemia, infectivity
Shock.
7. the application of 2- benzals -1- indone analogs according to claim 5, which is characterized in that the 2- benzal
Base -1- indones analog plays anti-inflammatory effect by inhibiting proinflammatory factor IL-6 and TNF-α.
8. the application of 2- benzals -1- indone analogs according to claim 5, which is characterized in that the 2- benzal
Base -1- indones analog is used to inhibit the expression of mRNA in inflammatory cell and play anti-inflammatory effect.
9. a kind of pharmaceutical preparation, including active ingredient and pharmaceutic adjuvant, which is characterized in that the active ingredient will including right
Seek 1~3 any one of them 2- benzal -1- indone analogs.
10. pharmaceutical preparation according to claim 9, which is characterized in that the pharmaceutical preparation is injection, tablet, glue
Wafer, aerosol, suppository, film, pill, ointment, controlled release agent, sustained release agent or nanometer formulation it is any.
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| CN114656454A (en) * | 2022-02-22 | 2022-06-24 | 温州医科大学 | 5-maleimide chromone compound and application thereof |
| CN114656454B (en) * | 2022-02-22 | 2023-10-20 | 温州医科大学 | 5-maleimide chromone compound and application thereof |
| CN115991688A (en) * | 2022-12-05 | 2023-04-21 | 中国科学院新疆理化技术研究所 | Heterocyclic orange ketone derivative and application thereof |
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